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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04009681




Registration number
NCT04009681
Ethics application status
Date submitted
27/06/2019
Date registered
5/07/2019

Titles & IDs
Public title
A Study Evaluating Safety and Therapeutic Activity of THOR-707 in Adult Subjects With Advanced or Metastatic Solid Tumors (THOR-707-101)
Scientific title
An Open-Label, Multicenter Phase 1/2 Dose Escalation and Expansion Study of THOR-707 as a Single Agent and as a Combination Therapy in Adult Subjects With Advanced or Metastatic Solid Tumors
Secondary ID [1] 0 0
U1111-1298-7281
Secondary ID [2] 0 0
THOR-707-101 (TCD16843)
Universal Trial Number (UTN)
Trial acronym
HAMMER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastasis 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - THOR-707
Treatment: Drugs - Checkpoint inhibitor
Treatment: Drugs - anti-EGFR antibody

Experimental: Cohort A-THOR-707 Q2W Monotherapy (Dose Escalation) - Subjects with advanced or metastatic solid tumors will receive THOR-707 in sequential ascending doses as a monotherapy via intravenous (IV) administration every 2 weeks (Q2W) until unacceptable toxicity, disease progression, or withdrawal of consent.

Experimental: Cohort B-THOR-707 Q3W Monotherapy (Dose Escalation) - Subjects with advanced or metastatic solid tumors will receive THOR-707 in sequential ascending doses as a monotherapy via IV administration every 3 weeks (Q3W) until unacceptable toxicity, disease progression, or withdrawal of consent.

Experimental: Cohort C-THOR-707 Q3W with checkpoint inhibitor (Dose Escalation) - Subjects with advanced or metastatic solid tumors will receive THOR-707 Q3W in sequential ascending doses in combination with a checkpoint inhibitor Q3W or every 6 weeks (Q6W) via IV administration until unacceptable toxicity, disease progression, or withdrawal of consent.

Experimental: Cohort D-THOR-707 Q3W with anti-EGFR antibody (Dose Escalation) - Subjects with advanced or metastatic solid tumors will receive THOR-707 Q3W in sequential ascending doses in combination with an anti-EGFR antibody weekly dosing (QW) via IV administration until unacceptable toxicity, disease progression, or withdrawal of consent.

Experimental: Cohort E-THOR-707 Q2W with checkpoint inhibitor (Dose Expansion) - Subjects with advanced or metastatic solid tumors will receiveTHOR-707 Q2W at recommended Phase 2 dose (RP2D) with a checkpoint inhibitor via IV administration Q6W; it will consist of one 8-week cycle of THOR-707 monotherapy on Cycle 1 Day 1 followed by THOR-707 Q2W + checkpoint inhibitor Q6W starting at Cycle 1 Day 15. Subsequently treatment will consist of repeated 6-week cycles with combination therapy.

Experimental: Cohort F-THOR-707 Q3W with checkpoint inhibitor (Dose Expansion) - Subjects with advanced or metastatic solid tumors will receive THOR-707 Q3W at recommended Phase 2 dose (RP2D) with a checkpoint inhibitor via IV administration Q6W will consist of one 9-week cycle of THOR monotherapy on Cycle 1 Day 1 followed by THOR-707 Q3W + checkpoint inhibitor at Cycle 1 Day 22. Subsequently treatment will consist of repeated 6-weeks cycles with combination therapy.

Experimental: Cohort G Monotherapy QW/Q2W (Dose Escalation) - Subjects with advanced or metastatic solid tumors will receive THOR707 monotherapy QW for 6 weeks (induction period), and then every Q2W (maintenance period), which is referred as QW/Q2W thereafter, until unacceptable toxicity, disease progression, or withdrawal of consent.

Experimental: Cohort H Monotherapy QW/Q2W (Dose Expansion) - Subjects with late-line metastatic melanoma will receive THOR707 monotherapy at RP2D for Cohort G. Cycle 1 will consist of THOR-707 QW for 6 weeks; Cycle 2 and beyond will consist of THOR-707 Q2W.


Treatment: Drugs: THOR-707
Pharmaceutical form: solution for intravenous (IV) administration; Route of administration: IV administration

Treatment: Drugs: Checkpoint inhibitor
Pharmaceutical form: solution for IV administration; Route of administration: IV administration

Treatment: Drugs: anti-EGFR antibody
Pharmaceutical form: solution for IV administration; Route of administration: IV administration
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Rate of Dose-Limiting Toxicities (DLTs)- Cohorts A, B, C, and D
Timepoint [1] 0 0
Study Day 1 up to Day 29
Primary outcome [2] 0 0
Maximum Tolerated Dose (MTD)- Cohorts A, B, C, and D
Timepoint [2] 0 0
Study Day 1 up to Day 29
Primary outcome [3] 0 0
Recommended Phase 2 Dose (RP2D)- Cohorts A, B, C, and D
Timepoint [3] 0 0
Study Day 1 up to Day 29
Primary outcome [4] 0 0
Number of participants with treatment emergent adverse events, serious adverse events, and laboratory abnormalities - Cohorts A, B, C, D, E, F, and G
Timepoint [4] 0 0
Study Day 1 up to approximately 24 months
Primary outcome [5] 0 0
Rate of Dose-Limiting Toxicities (DLTs) -Cohort G
Timepoint [5] 0 0
Study Day 1 up to Day 42 (6 week-cycle)
Primary outcome [6] 0 0
Recommended Phase 2 Dose (RP2D) of THOR-707- Cohort G
Timepoint [6] 0 0
Study Day 1 up to Day 42 (6 week-cycle)
Primary outcome [7] 0 0
Maximum Tolerated Dose (MTD)- Cohort G
Timepoint [7] 0 0
Study Day 1 up to Day 42 (6 week-cycle)
Primary outcome [8] 0 0
Objective Response Rate (ORR) according to RECIST version 1.1 -Cohort H
Timepoint [8] 0 0
Study Day 1 up to approximately 24 months
Secondary outcome [1] 0 0
Objective Response Rate (ORR) according to RECIST version 1.1 Cohort A, B, C, D, E, F, and G)
Timepoint [1] 0 0
Study Day 1 up to approximately 24 months
Secondary outcome [2] 0 0
Duration of Response (DOR) according to RECIST version 1.1
Timepoint [2] 0 0
Study Day 1 up to approximately 24 months
Secondary outcome [3] 0 0
Progression-Free Survival (PFS) according to RECIST version 1.1
Timepoint [3] 0 0
Study Day 1 until the date of first documented progression or date of death from any cause, assessed up to approximately 24 months
Secondary outcome [4] 0 0
Overall Survival according to RECIST version 1.1
Timepoint [4] 0 0
Study Day 1 up to time of death, assessed up to approximately 24 months
Secondary outcome [5] 0 0
Time to Response (TTR) according to RECIST version 1.1
Timepoint [5] 0 0
Study Day 1 up to approximately 24 months
Secondary outcome [6] 0 0
Disease Control Rate (DCR) according to RECIST version 1.1
Timepoint [6] 0 0
Study Day 1 up to approximately 24 months
Secondary outcome [7] 0 0
Percentage of subjects with no disease progression at 6 months post-treatment
Timepoint [7] 0 0
Approximately 6 months after the End of Treatment (EOT)
Secondary outcome [8] 0 0
Number of participants with treatment emergent adverse events, serious adverse events, laboratory abnormalities -Cohort H
Timepoint [8] 0 0
Study Day 1 up to approximately 24 months

Eligibility
Key inclusion criteria
Key

* Measurable disease per RECIST v1.1. For Cohort G participants must have at least 1 measurable lesion, and for Part 3 (Cohorts E, F and H) participants must have at least 2 measurable lesions to safely perform mandatory pre & on-treatment biopsy.
* Life expectancy greater than or equal to 12 weeks.
* For Part 2 exclusively: While it is highly preferred to enroll subjects who are naïve to PD-1 inhibitors into a Part 2 dose escalation cohort, this is not an enrollment requirement. However, subjects who enroll into a Part 2 safety expansion cohort must be naïve to PD-1 inhibitors. If such subject is unable to meet this requirement but otherwise remains a good candidate for study enrollment, the Investigator should discuss with the Sponsor whether the subject may be enrolled.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate cardiovascular, hematological, liver, and renal function.
* Histologically or cytologically confirmed diagnosis of advanced and/or metastatic solid tumors with at least one tumor lesion with location accessible to safely biopsy per clinical judgment of the Investigator.

* Caution: Cohort D only patients with KRAS mutant colon cancer have not typically benefitted from the addition of cetuximab in earlier lines of therapy.
* Caution: Cohorts E & F enrollment will include only patients with tumors for which anti-PD(L)1 as single agent or in combination treatments are approved.
* Caution: For Cohort H, the participant must have received at least one prior line of therapy for metastatic melanoma and/or does not have any standard of care (SoC) treatment option or participant declines or is intolerant to be treated with SoC treatment.
* Subjects with advanced or metastatic solid tumors who have refused SoC; or for whom no reasonable SoC exists that would confer clinical benefit; or for whom standard therapy is intolerable, not effective, or not accessible.
* Prior anti-cancer therapy is allowed as long as any treatment related toxicity is resolved to an appropriate level.
* Females of childbearing potential and men who are not surgically sterile must agree to use medically-accepted method of birth control during the study and for at least7 days (for Cohorts A, B, G and H), at least 2 months (for Cohort D), or at least 4 months (for Cohorts C, E and F) for females, and for at least 3 days for males [corresponding to the time needed to eliminate study intervention] after the last dose of study intervention.
* [Females] Negative serum pregnancy test within 7 days prior to initiating study treatment in premenopausal women and women less than 12 months after menopause.
* [Males] Agreement to refrain from donating or banking sperm during the treatment period and for at least 3 days after last dose of study treatment.
* In Spain, Chile, and Argentina: Only cohorts G and H will be open to enrollment.

Key
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Radiotherapy = 14 days prior to first dose of study drug (palliative radiation or stereotactic radiosurgery within 7 days prior to start of study treatment).
* Treated with systemic anti-cancer therapy or an investigational agent within 2 weeks prior to start of study drug treatment (within 4 weeks for immunotherapy and tyrosine kinase inhibitor therapy).
* Subjects who experienced Grade 3 or higher immune-related toxicity from prior immuno-oncology therapy.
* Major surgery = 30 days prior to first dose of study drug, or has not recovered to at least Grade 1 from adverse effects from such procedure, or anticipation of the need for major surgery during study treatment.
* Active autoimmune disease requiring systemic treatment within the past 3 months or have a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents.
* Primary central nervous system (CNS) disease or leptomeningeal disease; known CNS metastases unless treated, are asymptomatic, are without evidence of radiological progression for at least 8 weeks, and have had no requirement for steroids or enzyme inducing anticonvulsants in the last 14 days prior to Screening.
* Abnormal pulmonary function within the previous 6 months, including pneumonitis, active pneumonitis, interstitial lung disease requiring the use of steroids, idiopathic pulmonary fibrosis, confirmed pleural effusion, severe dyspnea at rest or requiring supplementary oxygen therapy.
* Parenteral antibiotics within 14 days of the first dose of study drug.
* History of allogenic or solid organ transplant.
* Uncontrolled diabetes mellitus or other uncontrolled immune-related endocrinopathies in the opinion of the Investigator.
* Known human immunodeficiency virus (HIV) infection or active infection with hepatitis C.
* For known uncontrolled hepatitis B virus (HBV) infection:

i. Anti-HBV therapy started before initiation of IMP and HBV viral load <2000 IU/mL (104 copies/mL) are eligible. The anti-HBV therapy should continue throughout the treatment period. ii. Positive anti-HBc, positive anti HBs, negative HBsAg, and HBV virus load without HBV therapy are eligible.
* Received a live-virus vaccination =14 days prior to first dose of study drug. Seasonal flu and other inactivated vaccines that do not contain live virus are permitted.
* Clinically significant bleeding within 2 weeks prior to initial THOR-707 dose (e.g., gastrointestinal bleeding, intracranial hemorrhage).
* Prior diagnosis of deep vein thrombosis or pulmonary embolism within 3 months.
* Severe or unstable cardiac condition within 6 months prior to starting study treatment, such as congestive heart failure (New York Heart Association Class III or IV), cardiac bypass surgery or coronary artery stent placement, angioplasty, cardiac ejection fraction below the lower limit of normal, unstable angina, medically uncontrolled hypertension (e.g. =160 mm Hg systolic or =100 mm Hg diastolic), uncontrolled cardiac arrhythmia requiring medication (= grade 2, according to NCI CTCAE v5.0), or myocardial infarction.
* History of non-pharmacologically induced prolonged corrected QT interval determined using Fridericia's formula (QTcF) > 450 milliseconds (msec) in males or > 470 msec in females.
* Known hypersensitivity or contraindications to any components of THOR-707, PEG, pegylated drugs, and E. coli derived-protein, checkpoint inhibitor, or anti-EGFR antibody for applicable cohorts.
* Active second malignancy, or history of previous malignancy that would impact the assessment of any study endpoints. Subjects with non-melanomatous skin cancer or cervical cancer that has been curatively surgically resected are eligible.
* Any serious medical condition (including pre-existing autoimmune disease or inflammatory disorder), laboratory abnormality, psychiatric condition, or any other significant or unstable concurrent medical illness that in the opinion of the Investigator would preclude protocol therapy or would make the subject inappropriate for the study.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through for at least 7 days (for Cohorts A, B, G, and H), at least 2 months (for Cohort D), or at least 4 months (for Cohorts C, E, and F) for females and for at least 3 days for males [corresponding to the time needed to eliminate study intervention] after the last dose of study intervention.
* Concurrent therapy with any other investigational agent, vaccine, or device. Concomitant participation in observational studies is acceptable after Sponsor approval.
* For Cohort D only: patients with symptomatic keratitis and/or symptomatic dry eye should be excluded from enrollment. Patients who wear contact lenses should be advised to avoid contact lenses use as it could result in keratitis.
* Subjects with baseline oxygen saturation <92% are not eligible for enrollment.
* For participants in Cohort H: Participants with uveal or ocular or desmoplastic metastatic melanoma.

The above information is not intended to contain all considerations relevant to the potential participation in a clinical trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
20/06/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2026
Actual
Sample size
Target
250
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Investigational Site Number-2004 - New South Whales
Recruitment hospital [2] 0 0
Investigational Site Number-2001 - Perth
Recruitment hospital [3] 0 0
Investigational Site Number-2002 - Victoria
Recruitment hospital [4] 0 0
Investigational Site Number-2003 - Victoria
Recruitment postcode(s) [1] 0 0
- New South Whales
Recruitment postcode(s) [2] 0 0
- Perth
Recruitment postcode(s) [3] 0 0
- Victoria
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Tennessee
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
Argentina
State/province [6] 0 0
Buenos Aires
Country [7] 0 0
Chile
State/province [7] 0 0
Santiago
Country [8] 0 0
Singapore
State/province [8] 0 0
Singapore
Country [9] 0 0
Spain
State/province [9] 0 0
Barcelona
Country [10] 0 0
Spain
State/province [10] 0 0
Madrid

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Synthorx, Inc, a Sanofi company
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Sciences & Operations
Address 0 0
Sanofi
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Trial Transparency email recommended Toll Free Number for US and Canada
Address 0 0
Country 0 0
Phone 0 0
800-633-1610
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org.
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04009681